Cyclic dinucleotides for treating conditions associated with STING activity such as cancer

ABSTRACT

This disclosure features chemical entities (e.g., a compound that modulates (e.g., agonizes) Stimulator of Interferon Genes (STING), or a pharmaceutically acceptable salt, and/or hydrate, and/or coccrystal, and/or drug combination of the compound) that are useful, e.g., for treating a condition, disease or disorder in which a decrease or increase in STING activity (e.g., a decrease, e.g., a condition, disease or disorder associated with repressed or impaired STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/277,273, filed on Jan. 11, 2016 and U.S. Provisional Application No.62/436,795, filed on Dec. 20, 2016, each of which is incorporated hereinby reference in its entirety.

TECHNICAL FIELD

This disclosure features chemical entities (e.g., a compound thatmodulates (e.g., agonizes) Stimulator of Interferon Genes (STING), or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that are useful, e.g., fortreating a condition, disease or disorder in which a decrease orincrease in STING activity (e.g., a decrease, e.g., a condition, diseaseor disorder associated with repressed or impaired STING signaling)contributes to the pathology and/or symptoms and/or progression of thecondition, disease or disorder (e.g., cancer) in a subject (e.g., ahuman). This disclosure also features compositions as well as othermethods of using and making the same.

BACKGROUND

STING, also known as transmembrane protein 173 (TMEM173) andMPYS/MITA/ERIS, is a protein that in humans is encoded by the TMEM173gene. STING has been shown to play a role in innate immunity. STINGinduces type I interferon production when cells are infected withintracellular pathogens, such as viruses, mycobacteria and intracellularparasites. Type I interferon, mediated by STING, protects infected cellsand nearby cells from local infection in an autocrine and paracrinemanner. The STING pathway is a pathway that is involved in the detectionof cytosolic DNA.

The STING signaling pathway is activated by cyclic dinucleotides (CDNs),which may be produced by bacteria or produced by antigen presentingcells in response to sensing cytosolic DNA. Unmodified CDNs have beenshown to induce type I interferon and other co-regulated genes, which inturn facilitate the development of a specific immune response (see,e.g., Wu and Sun, et al., Science 2013, 339, 826-830). WO 2015/077354discloses the use of STING agonists for the treatment of cancer.

SUMMARY

This disclosure features chemical entities (e.g., a compound thatmodulates (e.g., agonizes) Stimulator of Interferon Genes (STING), or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that are useful, e.g., fortreating a condition, disease or disorder in which a decrease orincrease in STING activity (e.g., a decrease, e.g., a condition, diseaseor disorder associated with repressed or impaired STING signaling)contributes to the pathology and/or symptoms and/or progression of thecondition, disease or disorder (e.g., cancer) in a subject (e.g., ahuman). In certain embodiments, the chemical entities described hereininduce an immune response in a subject (e.g., a human). In certainembodiments, the chemical entities described herein induceSTING-dependent type I interferon production in a subject (e.g., ahuman). This disclosure also features compositions as well as othermethods of using and making the same.

An “agonist” of STING includes compounds that, at the protein level,directly bind or modify STING such that an activity of STING isincreased, e.g., by activation, stabilization, altered distribution, orotherwise.

Certain compounds described herein that agonize STING to a lesser extentthan a STING full agonist can function in assays as antagonists as wellas agonists. These compounds antagonize activation of STING by a STINGfull agonist because they prevent the full effect of STING interaction.However, the compounds also, on their own, activate some STING activity,typically less than a corresponding amount of the STING full agonist.Such compounds may be referred to as “partial agonists of STING”.

In some embodiments, the compounds described herein are agonists (e.g.full agonists) of STING. In other embodiments, the compounds describedherein are partial agonists of STING.

Generally, a receptor exists in an active (Ra) and an inactive (Ri)conformation. Certain compounds that affect the receptor can alter theratio of Ra to Ri (Ra/Ri). For example, a full agonist increases theratio of Ra/Ri and can cause a “maximal”, saturating effect. A partialagonist, when bound to the receptor, gives a response that is lower thanthat elicited by a full agonist (e.g., an endogenous agonist). Thus, theRa/Ri for a partial agonist is less than for a full agonist. However,the potency of a partial agonist may be greater or less than that of thefull agonist.

While not wishing to be bound by theory, it is believed that the partialagonists of STING described herein provide advantages with regard totreating the disorders described herein. By way of example, the partialagonists of STING described herein exhibit intrinsic activities that areexpected to be both (i) high enough to induce an anti-tumor response(i.e., kill one or more tumor cells) and (ii) low enough to reduce thelikelihood of producing toxicity-related side effects. As discussedabove, partial agonists can antagonize activation of STING by a STINGfull agonist because they prevent the full effect of STING interaction,thereby reducing the activity of the STING full agonist. It is believedthat this antagonism can also modulate (e.g., reduce) the toxicityprofile of the STING full agonist. Accordingly, this disclosurecontemplates methods in which the partial agonists of STING describedherein are combined with one (or more) full agonists of STING (e.g., asdescribed anywhere herein) to provide therapeutic drug combinations thatare both efficacious and exhibit relatively low toxicity.

In one aspect, compounds of Formula A, or a pharmaceutically acceptablesalt thereof, are featured:

in which A, B, X, X′, G¹, G², X¹, X², X³, X⁴, X⁵, X⁶, L¹, L², R_(1A),R_(1B), R_(2A), and R_(2B) can be as defined anywhere herein. X¹ and X⁵can each be independently “up” or “down.”

In another aspect, compounds of Formula B, or a pharmaceuticallyacceptable salt thereof, are featured:

in which A, B, X, X′, G¹, G², X¹, X², X³, X⁴, X⁵, X⁶, L¹, L², R_(1A),R_(1B), R_(2A), and R_(2B) can be as defined anywhere herein. X¹ and X⁵can each be independently “up” or “down.”

In one aspect, compounds of Formula I, or a pharmaceutically acceptablesalt thereof, are featured:

in which A, B, X, X′, G¹, G², X¹, X², X³, X⁴, X⁵, X⁶, L¹, L², R_(1A),R_(1B), R_(2A), and R_(2B) can be as defined anywhere herein.

In one aspect, compounds of Formula A′, or a pharmaceutically acceptablesalt thereof, are featured:

in which A, B, X, X′, X¹, X², X³, X⁴, X⁵, X⁶, L¹, L², R_(1A), R_(1B),R_(2A), and R_(2B) can be as defined anywhere herein. X¹ and X⁵ can eachbe independently “up” or “down.”

In another aspect, compounds of Formula B′, or a pharmaceuticallyacceptable salt thereof, are featured:

in which A, B, X, X′, X¹, X², X³, X⁴, X⁵, X⁶, L¹, L², R_(1A), R_(1B),R_(2A), and R_(2B) can be as defined anywhere herein. X′ and X⁵ can eachbe independently “up” or “down.”

In another aspect, compounds of Formula I-A, or a pharmaceuticallyacceptable salt thereof, are featured:

in which A, B, X, X′, X¹, X², X³, X⁴, X⁵, X⁶, L¹, L², R_(1A), R_(1B),R_(2A), and R_(2B) can be as defined anywhere herein.

In one aspect, pharmaceutical compositions are featured that include achemical entity described herein (e.g., a compound described genericallyor specifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same) and one or more pharmaceuticallyacceptable excipients.

In one aspect, methods for modulating (e.g., agonizing) STING activityare featured that include contacting STING with a chemical entitydescribed herein (e.g., a compound described generically or specificallyherein or a pharmaceutically acceptable salt thereof or compositionscontaining the same). Methods include in vitro methods, e.g., contactinga sample that includes one or more cells comprising STING (e.g., innateimmune cells, e.g., mast cells, macrophages, dendritic cells (DCs), andnatural killer cells) with the chemical entity. The contacting can, insome cases, induce an immune response sufficient to kill at least one ofthe one or more cancer cells. Methods can also include in vivo methods;e.g., administering the chemical entity to a subject (e.g., a human)having a disease in which repressed or impaired STING signalingcontributes to the pathology and/or symptoms and/or progression of thedisease (e.g., cancer; e.g., a refractory cancer).

In another aspect, methods of treating cancer are featured that includeadministering to a subject in need of such treatment an effective amountof a chemical entity described herein (e.g., a compound describedgenerically or specifically herein or a pharmaceutically acceptable saltthereof or compositions containing the same).

In a further aspect, methods of inducing an immune response (e.g., aninnate immune response) in a subject in need thereof are featured thatinclude administering to the subject an effective amount of a chemicalentity described herein (e.g., a compound described generically orspecifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same).

In another aspect, methods of inducing induce STING-dependent type Iinterferon production in a subject in need thereof are featured thatinclude administering to the subject an effective amount of a chemicalentity described herein (e.g., a compound described generically orspecifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same).

In a further aspect, methods of treatment of a disease in whichrepressed or impaired STING signaling contributes to the pathologyand/or symptoms and/or progression of the disease are featured thatinclude administering to a subject in need of such treatment aneffective amount of a chemical entity described herein (e.g., a compounddescribed generically or specifically herein or a pharmaceuticallyacceptable salt thereof or compositions containing the same).

In another aspect, methods of treatment are featured that includeadministering to a subject having a disease in which repressed orimpaired STING signaling contributes to the pathology and/or symptomsand/or progression of the disease an effective amount of a chemicalentity described herein (e.g., a compound described generically orspecifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same).

In a further aspect, methods of treatment that include administering toa subject a chemical entity described herein (e.g., a compound describedgenerically or specifically herein or a pharmaceutically acceptable saltthereof or compositions containing the same), wherein the chemicalentity is administered in an amount effective to treat a disease inwhich repressed or impaired STING signaling contributes to the pathologyand/or symptoms and/or progression of the disease, thereby treating thedisease.

Embodiments can include one or more of the following features.

The chemical entity can be administered in combination with one or moreadditional cancer therapies (e.g., surgery, radiotherapy, chemotherapy,toxin therapy, immunotherapy, cryotherapy or gene therapy, or acombination thereof; e.g., chemotherapy that includes administering oneor more (e.g., two, three, four, five, six, or more) additionalchemotherapeutic agents. Non-limiting examples of additionalchemotherapeutic agents is selected from an alkylating agent (e.g.,cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil,ifosfamide and/or oxaliplatin); an anti-metabolite (e.g., azathioprineand/or mercaptopurine); a terpenoid (e.g., a vinca alkaloid and/or ataxane; e.g., Vincristine, Vinblastine, Vinorelbine and/or VindesineTaxol, Pacllitaxel and/or Docetaxel); a topoisomerase (e.g., a type Itopoisomerase and/or a type 2 topoisomerase; e.g., camptothecins, suchas irinotecan and/or topotecan; amsacrine, etoposide, etoposidephosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin,anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin,epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., alutenizing hormone releasing hormone agonist; e.g., leuprolidine,goserelin, triptorelin, histrelin, bicalutamide, flutamide and/ornilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab,Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin,Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab,Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Golimumab, Ibritumomabtiuxetan, Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab,Ofatumumab, Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab,Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent;a cytokine; a thrombotic agent; a growth inhibitory agent; ananti-helminthic agent; and an immune checkpoint inhibitor that targetsan immune checkpoint receptor selected from the group consisting ofCTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, interleukin-2 (IL-2),indoleamine 2,3-dioxygenase (IDO), IL-10, transforming growth factor-β(TGFβ), T cell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin9-TIM3, Phosphatidylserine-TIM₃, lymphocyte activation gene 3 protein(LAG3), MHC class II-LAG3, 4-IBB-4-IBB ligand, OX40-OX40 ligand, GITR,GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L,CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160,HVEM-LIGHT, LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244,CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H₃, B7-H4, VISTA, TMIGD2,HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family, TIGIT andPVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB,CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73Adenosine-CD39-CD73, CXCR4-CXCL12, Phosphatidylserine, TIM3,Phosphatidylserine-TIM₃, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, andCD155 (e.g., CTLA-4 or PD1 or PD-L1).

The subject can have cancer; e.g., the subject has undergone and/or isundergoing and/or will undergo one or more cancer therapies.

Non-limiting examples of cancer include melanoma, cervical cancer,breast cancer, ovarian cancer, prostate cancer, testicular cancer,urothelial carcinoma, bladder cancer, non-small cell lung cancer, smallcell lung cancer, sarcoma, colorectal adenocarcinoma, gastrointestinalstromal tumors, gastroesophageal carcinoma, colorectal cancer,pancreatic cancer, kidney cancer, hepatocellular cancer, malignantmesothelioma, leukemia, lymphoma, myelodysplasia syndrome, multiplemyeloma, transitional cell carcinoma, neuroblastoma, plasma cellneoplasms, Wilm's tumor, or hepatocellular carcinoma. In certainembodiments, the cancer can be a refractory cancer.

The chemical entity can be administered intratumorally.

The methods can further include identifying the subject.

Other embodiments include those described in the Detailed Descriptionand/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a numberof additional terms are defined below. Generally, the nomenclature usedherein and the laboratory procedures in organic chemistry, medicinalchemistry, and pharmacology described herein are those well-known andcommonly employed in the art. Unless defined otherwise, all technicaland scientific terms used herein generally have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. Each of the patents, applications, publishedapplications, and other publications that are mentioned throughout thespecification are incorporated herein by reference in their entireties.

As used herein, the term “STING” is meant to include, withoutlimitation, nucleic acids, polynucleotides, oligonucleotides, sense andantisense polynucleotide strands, complementary sequences, peptides,polypeptides, proteins, homologous and/or orthologous STING molecules,isoforms, precursors, mutants, variants, derivatives, splice variants,alleles, different species, and active fragments thereof.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of a chemical entity (e.g., acompound exhibiting activity as a mitochondrial uncoupling agent or apharmaceutically acceptable salt and/or hydrate and/or cocrystalthereof; e.g., a compound, such as niclosamide or a pharmaceuticallyacceptable salt and/or hydrate and/or cocrystal thereof; e.g., acompound, such as a niclosamide analog, or a pharmaceutically acceptablesalt and/or hydrate and/or cocrystal thereof) being administered whichwill relieve to some extent one or more of the symptoms of the diseaseor condition being treated. The result includes reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in disease symptoms. An appropriate “effective”amount in any individual case is determined using any suitabletechnique, such as a dose escalation study.

The term “excipient” or “pharmaceutically acceptable excipient” means apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, carrier, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. See,e.g., Remington: The Science and Practice of Pharmacy, 21st ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook ofPharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; ThePharmaceutical Press and the American Pharmaceutical Association: 2009;Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In certain instances, pharmaceuticallyacceptable salts are obtained by reacting a compound described herein,with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. In some instances,pharmaceutically acceptable salts are obtained by reacting a compoundhaving acidic group described herein with a base to form a salt such asan ammonium salt, an alkali metal salt, such as a sodium or a potassiumsalt, an alkaline earth metal salt, such as a calcium or a magnesiumsalt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts withamino acids such as arginine, lysine, and the like, or by other methodspreviously determined. The pharmacologically acceptable salt s notspecifically limited as far as it can be used in medicaments. Examplesof a salt that the compounds described hereinform with a base includethe following: salts thereof with inorganic bases such as sodium,potassium, magnesium, calcium, and aluminum; salts thereof with organicbases such as methylamine, ethylamine and ethanolamine; salts thereofwith basic amino acids such as lysine and ornithine; and ammonium salt.The salts may be acid addition salts, which are specifically exemplifiedby acid addition salts with the following: mineral acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, and phosphoric acid:organic acids such as formic acid,acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic aminoacids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components (referred tocollectively herein as “excipients”), such as carriers, stabilizers,diluents, dispersing agents, suspending agents, and/or thickeningagents. The pharmaceutical composition facilitates administration of thecompound to an organism. Multiple techniques of administering a compoundexist in the art including, but not limited to: rectal, oral,intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topicaladministration.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat,rabbit, rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human.

The terms “treat,” “treating,” and “treatment,” in the context oftreating a disease or disorder, are meant to include alleviating orabrogating a disorder, disease, or condition, or one or more of thesymptoms associated with the disorder, disease, or condition; or toslowing the progression, spread or worsening of a disease, disorder orcondition or of one or more symptoms thereof. The “treatment of cancer”,refers to one or more of the following effects: (1) inhibition, to someextent, of tumor growth, including, (i) slowing down and (ii) completegrowth arrest; (2) reduction in the number of tumor cells; (3)maintaining tumor size; (4) reduction in tumor size; (5) inhibition,including (i) reduction, (ii) slowing down or (iii) complete prevention,of tumor cell infiltration into peripheral organs; (6) inhibition,including (i) reduction, (ii) slowing down or (iii) complete prevention,of metastasis; (7) enhancement of anti-tumor immune response, which mayresult in (i) maintaining tumor size, (ii) reducing tumor size, (iii)slowing the growth of a tumor, (iv) reducing, slowing or preventinginvasion and/or (8) relief, to some extent, of the severity or number ofone or more symptoms associated with the disorder.

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo(I).

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, C₁₋₁₀ indicates that the group may have from 1 to 10(inclusive) carbon atoms in it. Non-limiting examples include methyl,ethyl, iso-propyl, tert-butyl, n-hexyl.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogenatoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH₃).

The term “alkylene” refers to a divalent alkyl (e.g., —CH₂—).

The term “alkenyl” refers to a hydrocarbon chain that may be a straightchain or branched chain having one or more carbon-carbon double bonds.The alkenyl moiety contains the indicated number of carbon atoms. Forexample, C₂₋₆ indicates that the group may have from 2 to 6 (inclusive)carbon atoms in it.

The term “alkynyl” refers to a hydrocarbon chain that may be a straightchain or branched chain having one or more carbon-carbon triple bonds.The alkynyl moiety contains the indicated number of carbon atoms. Forexample, C₂₋₆ indicates that the group may have from 2 to 6 (inclusive)carbon atoms in it.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic, or14-carbon tricyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atomsof each ring may be substituted by a substituent. Examples of arylgroups include phenyl, naphthyl and the like.

The term “cycloalkyl” as used herein includes saturated cyclichydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons,and more preferably 3 to 6 carbons, wherein the cycloalkyl group may beoptionally substituted. Preferred cycloalkyl groups include, withoutlimitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3,or 4 atoms of each ring may be substituted by a substituent. Examples ofheteroaryl groups include pyridyl, furyl or furanyl, imidazolyl,benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl,thiazolyl, and the like.

The term “heterocyclyl” refers to a nonaromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3atoms of each ring may be substituted by a substituent. Examples ofheterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl,morpholinyl, tetrahydrofuranyl, and the like.

In addition, atoms making up the compounds of the present embodimentsare intended to include all isotopic forms of such atoms. Isotopes, asused herein, include those atoms having the same atomic number butdifferent mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium, andisotopes of carbon include ¹³C and ¹⁴C.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features andadvantages of the invention will be apparent from the description anddrawings, and from the claims.

DETAILED DESCRIPTION

This disclosure features chemical entities (e.g., a compound thatmodulates (e.g., agonizes) Stimulator of Interferon Genes (STING), or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that are useful, e.g., fortreating a condition, disease or disorder in which a decrease orincrease in STING activity (e.g., a decrease, e.g., a condition, diseaseor disorder associated with repressed or impaired STING signaling)contributes to the pathology and/or symptoms and/or progression of thecondition, disease or disorder (e.g., cancer) in a subject (e.g., ahuman). In certain embodiments, the chemical entities described hereininduce an immune response in a subject (e.g., a human). In certainembodiments, the chemical entities described herein induceSTING-dependent type I interferon production in a subject (e.g., ahuman). This disclosure also features compositions as well as othermethods of using and making the same.

Formula I Compounds

In one aspect, compounds of Formula A, or a pharmaceutically acceptablesalt thereof,

wherein:

A and B are each independently selected from the group consisting ofFormulae (i), (ii), (iii), and (iv):

X and X′ are each independently selected from the group consisting of O,S, S(O), SO₂, CH₂, CHF, CF₂, CH₂O, OCH₂, CH₂CH₂, CH═CH, NR³, andN(O⁻)R³;

G¹ is a bond connecting (i) the carbon directly attached to X² and (ii)the carbon directly attached to C(R^(2A))(R^(2B))(X⁶), or isC(R^(G1A))(R^(G1B));

G² is a bond connecting (i) the carbon directly attached to X⁴ and (ii)the carbon directly attached to C(R^(1A))(R^(1B))(C³); or isC(R^(G2A))(R^(G2B))(X³); or is C(R^(G2A))(R^(G2B));

X¹ and X⁵ are each independently selected from the group consisting ofH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo (e.g., F), —CN, —NO₂, —N₃, —OH,—OR^(a1), —SH, —C(O)H, —C(O)R^(a1), —C(O)NR^(c1)R^(d1), —C(O)OH,—C(O)OR^(a1), —OC(O)H, —OC(O)R^(a1), —OC(O)NR^(b1)R^(c1),—C(═NR^(e1))NR^(b1)R^(c1), —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), —NR^(d1)S(O)₂NR^(b1)R^(c1),—S(O)R^(a1), —S(O)NR^(b1)R^(c1), —S(O)₂R^(a1), and —S(O)₂NR^(b1)R^(c1);

X², X³, X⁴ and X⁶ are each independently selected from the groupconsisting of O and S;

L¹ is

L² is

Y¹ and Y² are each independently selected from the group consisting of—OH, —OR^(a1), O⁻, —SH, —SR^(a1), S⁻; —NR^(b1)R^(c1);

R^(1A) and R^(1B) are each independently selected from the groupconsisting of H; halo; C₁₋₄ alkyl; C₁₋₄ haloalkyl; C₂₋₄ alkenyl; C₂₋₄alkynyl; and C₃₋₅ cycloalkyl, which is optionally substituted with from1-4 independently selected C₁₋₄ alkyl; or R^(1A) and R^(1B), togetherwith the carbon atom to which each is attached, form a C₃₋₅ cycloalkylor heterocyclyl, including from 4-5 ring atoms, wherein from 1-2(e.g., 1) ring atoms are independently selected from the groupconsisting of nitrogen and oxygen (e.g oxetane), wherein the C₃₋₅cycloalkyl or heterocyclyl ring can each be optionally substituted withfrom 1-4 independently selected C₁₋₄ alkyl;

R^(2A) and R^(2B) are each independently selected from the groupconsisting of H; halo; C₁₋₄ alkyl; C₁₋₄ haloalkyl; C₂₋₄ alkenyl; C₂₋₄alkynyl; and C₃₋₅ cycloalkyl, which is optionally substituted with from1-4 independently selected C₁₋₄ alkyl; or R^(2A) and R^(2B), togetherwith the carbon atom to which each is attached, form a C₃₋₅ cycloalkylor heterocyclyl, including from 4-5 ring atoms, wherein from 1-2(e.g., 1) ring atoms are independently selected from the groupconsisting of nitrogen and oxygen (e.g., oxetane), wherein the C₃₋₅cycloalkyl or heterocyclyl ring can each be optionally substituted withfrom 1-4 independently selected C₁₋₄ alkyl,

Z₁ is N or C—R⁴;

Z_(1′) is N or C—H;

Z₂ is N or C—R^(4′);

Z_(2′) is N or C—H;

Z₃ is N—R³ or C—R⁴;

each occurrence of R^(a1) is independently selected from the groupconsisting of:

-   -   C₁₋₁₀ alkyl optionally substituted with from 1-3 R^(A);    -   C₁₋₁₀ haloalkyl optionally substituted with from 1-3 R^(A);    -   C₂₋₁₀ alkenyl optionally substituted with from 1-3 R^(B),    -   C₂₋₁₀ alkynyl optionally substituted with from 1-3 R^(B),    -   C₃₋₁₀ cycloalkyl optionally substituted with from 1-5 R^(C);    -   (C₃₋₁₀ cycloalkyl)-C₁₋₆ alkylene, wherein the alkylene serves as        the point of attachment, and wherein the C₃₋₁₀ cycloalkyl        optionally substituted with from 1-5 R^(C);    -   heterocyclyl, including from 3-10 ring atoms, wherein from 1-3        ring atoms are independently selected from the group consisting        of nitrogen, oxygen and sulfur, and which is optionally        substituted with from 1-5 R^(C);    -   (heterocyclyl as defined above)-C₁₋₆ alkylene, wherein the        alkylene serves as the point of attachment, and wherein the        heterocyclyl is optionally substituted with from 1-5 R^(C);    -   C₆₋₁₀ aryl optionally substituted with from 1-5 R^(D);    -   heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring        atoms are independently selected from the group consisting of        nitrogen, oxygen and sulfur, and which is optionally substituted        with from 1-5 R^(D); and    -   (heteroaryl as defined above)-C₁₋₆ alkylene, wherein the        alkylene serves as the point of attachment, and wherein the        heteroaryl optionally substituted with from 1-5 R^(D);

each occurrence of R³, R^(b1), R^(c1), R^(d1), and R^(c1) isindependently selected from the group consisting of: H; R^(a1); —C(O)H,—C(O)R^(a1), —C(O)NR^(c1)R^(d1), —C(O)OR^(a1), —OC(O)H,—C(═NR^(e1))NR^(b1)R^(c1), —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —S(O)R^(a1), —S(O)NR^(b1)R^(c1), —S(O)₂R^(a1), and—S(O)₂NR^(b1)R^(c1); or

R^(b1) and R^(c1) taken together with the nitrogen atom to which each isattached form a heterocyclyl, including from 3-10 ring atoms, whereinfrom 1-3 ring atoms are independently selected from the group consistingof nitrogen, oxygen and sulfur, and which is optionally substituted withfrom 1-5 R^(C); (e.g., azetidinyl, morpholino, piperidinyl);

each occurrence of R^(G1A), R^(G1B), R^(G1A), R^(G1B), R⁴, R^(4′), R⁵,R^(6′) is independently selected from the group consisting of: H;R^(a1); halo, —CN, —NO₂, —N₃, —OH, —OR^(a1), —SH, —SR^(a1), —C(O)H,—C(O)R^(a1), —C(O)NR^(c1)R^(d1), —C(O)OH, —C(O)OR^(a1), —OC(O)H,—OC(O)R^(a1), —OC(O)NR^(b1)R^(c1), —C(═NR^(e1))NR^(b1)R^(c1),—NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1), —N⁺R^(b1)R^(c1)R^(d1),—NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1), —NR^(c1)C(O)OR^(a1),—NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1),—NR^(d1)S(O)₂NR^(b1)R^(c1), —S(O)R^(a1), —S(O)NR^(b1)R^(c1),—S(O)₂R^(a1), and —S(O)₂NR^(b1)R^(c1);

each occurrence of R^(A) is independently selected from the groupconsisting of: —CN; —OH; C₁₋₆ alkoxy; C₁₋₆ haloalkoxy; —C(O)NRR′,wherein R′ and R″ are each independently selected from H and C₁₋₄ alkyl;—C(O)OH; —C(O)O(C₁₋₆ alkyl); and —NR′R′″, wherein R″ and R′″ are eachindependently selected from the group consisting of H, C₁₋₄ alkyl,—SO₂(C₁₋₆ alkyl), —C(O)(C₁₋₆ alkyl), and —C(O)O(C₁₋₆ alkyl);

each occurrence of R^(B) is independently selected from the groupconsisting of: halo; —CN; —OH; C₁₋₆ alkoxy; C₁₋₆ haloalkoxy; —C(O)NRR′,wherein R′ and R″ are each independently selected from H and C₁₋₄ alkyl;—C(O)OH; —C(O)O(C₁₋₆ alkyl); and —NR″R′″, wherein R′ and R′″ are eachindependently selected from the group consisting of H, C₁₋₄ alkyl,—SO₂(C₁₋₆ alkyl), —C(O)(C₁₋₆ alkyl), and —C(O)O(C₁₋₆ alkyl);

each occurrence of R^(C) is independently selected from the groupconsisting of: C₁₋₆ alkyl; C₁₋₄ haloalkyl; halo; —CN; —OH; oxo; C₁₋₆alkoxy; C₁₋₆ haloalkoxy; —C(O)NRR′, wherein R′ and R″ are eachindependently selected from H and C₁₋₄ alkyl; —C(O)(C₁₋₆ alkyl);—C(O)OH; —C(O)O(C₁₋₆ alkyl); and —NR′R′″, wherein R′ and R′″ are eachindependently selected from the group consisting of H, C₁₋₄ alkyl,—SO₂(C₁₋₆ alkyl), —C(O)(C₁₋₆ alkyl), and —C(O)O(C₁₋₆ alkyl);

each occurrence of R^(D) is independently selected from the groupconsisting of:

-   -   C₁₋₆ alkyl optionally substituted with from 1-2 substituents        independently selected from the group consisting of: —OH, C₁₋₄        alkoxy; C₁₋₄ haloalkoxy; —NH₂, —NH(C₁₋₄ alkyl), and —N(C₁₋₄        alkyl)₂;    -   C₁₋₄ haloalkyl;    -   C₂₋₄ alkenyl;    -   C₂₋₄ alkynyl;    -   halo;    -   —CN;    -   —NO₂;    -   —N₃;    -   —OH;    -   C₁₋₆ alkoxy;    -   C₁₋₆ haloalkoxy;    -   —C(O)NRR′, wherein R′ and R″ are each independently selected        from H and C₁₋₄ alkyl;    -   —SO₂NRR′, wherein R′ and R″ are each independently selected from        H and C₁₋₄ alkyl;    -   —C(O)(C₁₋₆ alkyl);    -   —C(O)OH;    -   —C(O)O(C₁₋₆ alkyl);    -   —SO₂(C₁₋₆ alkyl),    -   —NR″R′″, wherein R″ and R′″ are each independently selected from        the group consisting of H, C₁₋₄ alkyl, —SO₂(C₁₋₆ alkyl),        —C(O)(C₁₋₆ alkyl), and —C(O)O(C₁₋₆ alkyl);    -   (C₃₋₁₀ cycloalkyl)-(CH₂)₀₋₂, wherein the CH₂ (when present)        serves as the point of attachment, and wherein the C₃₋₁₀        cycloalkyl is optionally substituted with from 1-5 independently        selected C₁₋₄ alkyl;    -   (heterocyclyl as defined above)-(CH₂)₀₋₂, wherein the CH₂ (when        present) serves as the point of attachment, and wherein the        heterocyclyl is optionally substituted with from 1-5        independently selected C₁₋₄ alkyl;    -   (phenyl)-(CH₂)₀₋₂, wherein the CH₂ (when present) serves as the        point of attachment, and wherein the phenyl is optionally        substituted with from 1-5 substituents independently selected        from halo, C₁₋₄ alkyl, —CF₃, —OCH₃, —SCH₃, —OCF₃, —NO₂, —N₃,        —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —C(O)(C₁₋₄ alkyl),        —C(O)OH, —C(O)O(C₁₋₄ alkyl), —SO₂(CH₃), and cyclopropyl; and    -   (heteroaryl as defined above)-(CH₂)₀₋₂, wherein the CH₂ (when        present) serves as the point of attachment, and wherein the        phenyl is optionally substituted with from 1-5 substituents        independently selected from halo, C₁₋₄ alkyl, —CF₃, —OCH₃,        —SCH₃, —OCF₃, —NO₂, —N₃, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,        —C(O)(C₁₋₄ alkyl), —C(O)OH, —C(O)O(C₁₋₄ alkyl), —SO₂(CH₃), and        cyclopropyl.

In another aspect, of compounds having formula (A) can be as defined asfollows:

A and B are each independently selected from the group consisting ofFormulae (i), (ii), (iii), and (iv):

X and X′ are each independently selected from the group consisting of O,S, S(O), SO₂, CH₂, CHF, CF₂, CH₂O, OCH₂, CH₂CH₂, CH═CH, NR³, and N(O⁻)³;

G¹ is a bond connecting (i) the carbon directly attached to X² and (ii)the carbon directly attached to C(R^(2A))(R^(2B))(X⁶), or isC(R^(G1A))(R^(G1B));

G² is a bond connecting (i) the carbon directly attached to X⁴ and (ii)the carbon directly attached to C(R^(1A))(R^(1B))(X³); or isC(R^(G2A))(R^(G2B));

X¹ and X⁵ are each independently selected from the group consisting ofH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo (e.g., F), —CN, —NO₂, —N₃, —OH,—OR^(a1), —SH, —SR^(a1), —C(O)H, —C(O)R^(a1), —C(O)NR^(b1)R^(c1),—C(O)OH, —C(O)OR^(a1), —OC(O)H, —OC(O)R^(a1), —OC(O)NR^(b1)R^(c1),—C(═NR^(e1))NR^(b1)R^(c1), —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), —NR^(d1)S(O)₂NR^(b1)R^(c1),—S(O)R^(a1), —S(O)NR^(b1)R^(c1), —S(O)₂R^(a1), and —S(O)₂NR^(b1)R^(c1);

X², X³, X⁴ and X⁶ are each independently selected from the groupconsisting of O and S;

L¹ is

L² is

Y¹ and Y² are each independently selected from the group consisting of—OH, —OR^(a1), O⁻, —SH, —SR^(a1), S⁻; and —NR^(b1)R^(c1);

R^(1A) and R^(1B) are each independently selected from the groupconsisting of H; halo; C₁₋₄ alkyl; C₁₋₄ haloalkyl; C₂₋₄ alkenyl; C₂₋₄alkynyl; and C₃₋₅ cycloalkyl, which is optionally substituted with from1-4 independently selected C₁₋₄ alkyl; or R^(1A) and R^(1B), togetherwith the carbon atom to which each is attached, form a C₃₋₅ cycloalkylor heterocyclyl, including from 4-5 ring atoms, wherein from 1-2(e.g., 1) ring atoms are independently selected from the groupconsisting of nitrogen and oxygen (e.g oxetane), wherein the C₃₋₅cycloalkyl or heterocyclyl ring can each be optionally substituted withfrom 1-4 independently selected C₁₋₄ alkyl;

R^(2A) and R^(2B) are each independently selected from the groupconsisting of H; halo; C₁₋₄ alkyl; C₁₋₄ haloalkyl; C₂₋₄ alkenyl; C₂₋₄alkynyl; and C₃₋₅ cycloalkyl, which is optionally substituted with from1-4 independently selected C₁₋₄ alkyl; or R^(2A) and R^(2B), togetherwith the carbon atom to which each is attached, form a C₃₋₅ cycloalkylor heterocyclyl, including from 4-5 ring atoms, wherein from 1-2(e.g., 1) ring atoms are independently selected from the groupconsisting of nitrogen and oxygen (e.g., oxetane), wherein the C₃₋₅cycloalkyl or heterocyclyl ring can each be optionally substituted withfrom 1-4 independently selected C₁₋₄ alkyl,

Z₁ is N or C—R⁴;

Z_(1′) is N or C—H;

Z₂ is N or C—R^(4′);

Z_(2′) is N or C—H;

Z₃ is N—R³ or C—R⁴;

each occurrence of R^(a1) is independently selected from the groupconsisting of:

-   -   C₁₋₁₀ alkyl optionally substituted with from 1-3 R^(A);    -   C₁₋₁₀ haloalkyl optionally substituted with from 1-3 R^(A);    -   C₂₋₁₀ alkenyl optionally substituted with from 1-3 R^(B),    -   C₂₋₁₀ alkynyl optionally substituted with from 1-3 R^(B),    -   C₃₋₁₀ cycloalkyl optionally substituted with from 1-5 R^(C);    -   (C₃₋₁₀ cycloalkyl)-C₁₋₆ alkylene, wherein the alkylene serves as        the point of attachment, and wherein the C₃₋₁₀ cycloalkyl        optionally substituted with from 1-5 R^(C);    -   heterocyclyl, including from 3-10 ring atoms, wherein from 1-3        ring atoms are independently selected from the group consisting        of nitrogen, oxygen and sulfur, and which is optionally        substituted with from 1-5 R^(C);    -   (heterocyclyl as defined above)-C₁₋₆ alkylene, wherein the        alkylene serves as the point of attachment, and wherein the        heterocyclyl is optionally substituted with from 1-5 R^(C);    -   C₆₋₁₀ aryl optionally substituted with from 1-5 R^(D);    -   heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring        atoms are independently selected from the group consisting of        nitrogen, oxygen and sulfur, and which is optionally substituted        with from 1-5 R^(D); and    -   (heteroaryl as defined above)-C₁₋₆ alkylene, wherein the        alkylene serves as the point of attachment, and wherein the        heteroaryl optionally substituted with from 1-5 R^(D);

each occurrence of R^(b1) and R^(c1) is independently selected from thegroup consisting of: H; R^(a1); —C(O)H, —C(O)R^(a1), —C(O)NR^(b3)R^(c3);—C(O)OR^(a1), —OC(O)H, —C(═NR^(e2))NR^(b3)R^(c3), —NR²³C(═NR^(e2))NR^(b3)R^(c3), —NR^(b3)R^(c3), —S(O)R^(a1), —S(O) NR^(b3)R^(c3),—S(O)₂R^(a1), and —S(O)₂NR^(b3)R^(c3); or

R^(b1) and R^(c1) taken together with the nitrogen atom to which each isattached form a heterocyclyl, including from 3-10 ring atoms, whereinfrom 1-3 ring atoms are independently selected from the group consistingof nitrogen, oxygen and sulfur, and which is optionally substituted withfrom 1-5 R^(C); (e.g., azetidinyl, morpholino, piperidinyl);

each occurrence of R³, R^(d1), and R^(e1) is independently selected fromthe group consisting of: H; R^(a1); —C(O)H, —C(O)R^(a1),—C(O)NR^(b3)R^(c3), —C(O)OR^(a1), —OC(O)H, —C(═NR^(e2))NR^(b3)R^(c3),—NR^(d3)C(═NR^(e2))NR^(b3)R^(c3), —NR^(b3)R^(c3), —S(O)R^(a1),—S(O)NR^(b3)R^(c3), —S(O)₂R^(a1), and —S(O)₂NR^(b3)R^(c3);

each occurrence of R^(b2), R^(c2), and R^(d2) is independently selectedfrom the group consisting of: H and C₁₋₆ alkyl optionally substitutedwith from 1-2 R^(A);

each occurrence of R^(b3), R^(c3), R^(d3), and R^(e2) is independentlyselected from the group consisting of: H; C₁₋₆ alkyl optionallysubstituted with from 1-2 R^(A); —SO₂(C₁₋₆ alkyl), —C(O)(C₁₋₆ alkyl),and —C(O)O(C₁₋₆ alkyl);

each occurrence of R^(G1A), R^(G1B), R^(G1A), R^(G1B), R⁴, R^(4′), R⁵,R⁶, and R^(6′) is independently selected from the group consisting of:H; R^(a1); halo, —CN, —NO₂, —N₃, —OH, —OR^(a1), —SH, —SR^(a1), —C(O)H,—C(O)R^(a1), —C(O) NR^(b1)R^(c1), —C(O)OH, —C(O)OR^(a1), —OC(O)H,—OC(O)R^(a1), —OC(O)NR^(b1)R^(c1), —C(═NR^(e1))NR^(b1)R^(c1),—NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2),—NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1), —NR^(c1)C(O)OR^(a1),—NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1),—NR^(d1)S(O)₂NR^(b1)R^(c1), —S(O)R^(a1), —S(O)NR^(b1)R^(c1),—S(O)₂R^(a1), and —S(O)₂NR^(b1)R^(c1);

each occurrence of R^(A) is independently selected from the groupconsisting of: —CN; —OH; C₁₋₆ alkoxy; C₁₋₆ haloalkoxy; —C(O)NRR′,wherein R′ and R″ are each independently selected from H and C₁₋₄ alkyl;—C(O)OH; —C(O)O(C₁₋₆ alkyl); and —NR″R′″, wherein R″ and R′″ are eachindependently selected from the group consisting of H, C₁₋₄ alkyl,—SO₂(C₁₋₆ alkyl), —C(O)(C₁₋₆ alkyl), and —C(O)O(C₁₋₆ alkyl);

each occurrence of R^(B) is independently selected from the groupconsisting of: halo; —CN; —OH; C₁₋₆ alkoxy; C₁₋₆ haloalkoxy; —C(O)NRR′,wherein R′ and R″ are each independently selected from H and C₁₋₄ alkyl;—C(O)OH; —C(O)O(C₁₋₆ alkyl); and —NR″R′″, wherein R′ and R′″ are eachindependently selected from the group consisting of H, C₁₋₄ alkyl,—SO₂(C₁₋₆ alkyl), —C(O)(C₁₋₆ alkyl), and —C(O)O(C₁₋₆ alkyl);

each occurrence of R^(C) is independently selected from the groupconsisting of: C₁₋₆ alkyl; C₁₋₄ haloalkyl; halo; —CN; —OH; oxo; C₁₋₆alkoxy; C₁₋₆ haloalkoxy; —C(O)NRR′, wherein R′ and R′″ are eachindependently selected from H and C₁₋₄ alkyl; —C(O)(C₁₋₆ alkyl);—C(O)OH; —C(O)O(C₁₋₆ alkyl); and —NR″R′″, wherein R″ and R′″ are eachindependently selected from the group consisting of H, C₁₋₄ alkyl,—SO₂(C₁₋₆ alkyl), —C(O)(C₁₋₆ alkyl), and —C(O)O(C₁₋₆ alkyl);

each occurrence of R^(D) is independently selected from the groupconsisting of:

-   -   C₁₋₆ alkyl optionally substituted with from 1-2 substituents        independently selected from the group consisting of: —OH, C₁₋₄        alkoxy; C₁₋₄ haloalkoxy; —NH₂, —NH(C₁₋₄ alkyl), and —N(C₁₋₄        alkyl)₂;    -   C₁₋₄ haloalkyl;    -   C₂₋₄ alkenyl;    -   C₂₋₄ alkynyl;    -   halo;    -   —CN;    -   —NO₂;    -   —N₃;    -   —OH;    -   C₁₋₆ alkoxy;    -   C₁₋₆ haloalkoxy;    -   —C(O)NRR′, wherein R′ and R″ are each independently selected        from H and C₁₋₄ alkyl;    -   SO₂NRR′, wherein R′ and R″ are each independently selected from        H and C₁₋₄ alkyl;    -   —C(O)(C₁₋₆ alkyl);    -   —C(O)OH;    -   —C(O)O(C₁₋₆ alkyl);    -   —SO₂(C₁₋₆ alkyl),    -   —NR″R′″, wherein R″ and R′″ are each independently selected from        the group consisting of H, C₁₋₄ alkyl, —SO₂(C₁₋₆ alkyl),        —C(O)(C₁₋₆ alkyl), and —C(O)O(C₁₋₆ alkyl);    -   (C₃₋₁₀ cycloalkyl)-(CH₂)₀₋₂, wherein the CH₂ (when present)        serves as the point of attachment, and wherein the C₃₋₁₀        cycloalkyl is optionally substituted with from 1-5 independently        selected C₁₋₄ alkyl;    -   (heterocyclyl as defined above)-(CH₂)₀₋₂, wherein the CH₂ (when        present) serves as the point of attachment, and wherein the        heterocyclyl is optionally substituted with from 1-5        independently selected C₁₋₄ alkyl;    -   (phenyl)-(CH₂)₀₋₂, wherein the CH₂ (when present) serves as the        point of attachment, and wherein the phenyl is optionally        substituted with from 1-5 substituents independently selected        from halo, C₁₋₄ alkyl, —CF₃, —OCH₃, —SCH₃, —OCF₃, —NO₂, —N₃,        —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —C(O)(C₁₋₄ alkyl),        —C(O)OH, —C(O)O(C₁₋₄ alkyl), —SO₂(CH₃), and cyclopropyl;    -   (heteroaryl as defined above)-(CH₂)₀₋₂, wherein the CH₂ (when        present) serves as the point of attachment, and wherein the        phenyl is optionally substituted with from 1-5 substituents        independently selected from halo, C₁₋₄ alkyl, —CF₃, —OCH₃,        —SCH₃, —OCF₃, —NO₂, —N₃, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,        —C(O)(C₁₋₄ alkyl), —C(O)OH, —C(O)O(C₁₋₄ alkyl), —SO₂(CH₃), and        cyclopropyl; and

In some embodiments, one, two, three, four, five, six, seven, or eightof the following apply:

(a) X¹ and X⁵ cannot both be —OH:

(b) X¹ and X⁵ cannot both be halo (e.g., X¹ and X⁵ cannot both be —F);in certain embodiments, when A and B are each independently selectedfrom formula (i) and formula (ii), then X¹ and X⁵ cannot both be halo(e.g., X¹ and X⁵ cannot both be —F);

(c) X¹ and X⁵ cannot both be —OR^(a1) when each occurrence of R^(a1) isC₁₋₁₀ alkyl optionally substituted with from 1-3 R^(A) (e.g., when eachoccurrence of R^(a1) is C₁₋₄ alkyl optionally substituted with from 1-2R^(A); when each occurrence of R^(a1) is C₁₋₄ alkyl; e.g., when eachoccurrence of R^(a1) is methyl or ethyl);

(d) X¹ and X⁵ cannot both be —OR^(a1) when each occurrence of R^(a1) isheterocyclyl, including from 3-10 ring atoms, wherein from 1-3 ringatoms are independently selected from the group consisting of nitrogen,oxygen and sulfur, and which is optionally substituted with from 1-5R^(C); (in certain of these embodiments, the heterocyclyl, includes from5-7 ring atoms; e.g., 6 ring atoms, e.g., optionally substituted pyranylor piperidinyl);

(e) X¹ and X⁵ cannot both be —OR^(a1) when each occurrence of R^(a1) iswhen each occurrence of R^(a1) is (heterocyclyl as defined above)-C₁₋₆alkylene; in certain of these embodiments, the heterocyclyl, includesfrom 5-7 ring atoms; e.g., 6 ring atoms, e.g., optionally substitutedpyranyl or piperidinyl);

(f) X¹ and X⁵ cannot both be —OC(O)R^(a1) when each occurrence of R^(a1)is C₁₋₁₀ alkyl optionally substituted with from 1-3 R^(A) (e.g., wheneach occurrence of R^(a1) is C₁₋₄ alkyl optionally substituted with from1-2 R^(A); e.g., when each occurrence of R^(a1) is C₁₋₄ alkyl; e.g.,when each occurrence of R^(a1) is methyl);

(g) X¹ and X⁵ cannot both be —OC(O)R^(a1) when each occurrence of R^(a1)is C₆₋₁₀ aryl (e.g., phenyl) optionally substituted with from 1-5 R^(D);and

(h) when one of X¹ and X⁵ is —OH, then the other of X¹ and X⁵ cannot be:

-   -   halo (e.g., —F);    -   OC(O)NR^(b1)R^(c1);    -   OC(O)R^(a1) (e.g., when each occurrence of R^(a1) is C₆₋₁₀ aryl        (e.g., phenyl) optionally substituted with from 1-5 R^(D)); or    -   —OR^(a1) (e.g., when each occurrence of R^(a1) is C₁₋₁₀ alkyl        optionally substituted with from 1-3 R^(A) (e.g., when each        occurrence of R^(a1) is C₁₋₄ alkyl optionally substituted with        from 1-2 R^(A); when each occurrence of R^(a1) is C₁₋₄ alkyl;        e.g., when each occurrence of R^(a1) is methyl or ethyl).

Variables X, X′, G¹, and G¹

In some embodiments, the compounds have formula (B). In someembodiments, the compounds have formula (I).

In some embodiments, X and X′ are each O. In some embodiments, G¹ is abond connecting (i) the carbon directly attached to X² and (ii) thecarbon directly attached to C(R^(2A))(R^(2B))(X⁶). In some embodiments,G² is a bond connecting (i) the carbon directly attached to X⁴ and (ii)the carbon directly attached to C(R^(1A))(R^(1B))(X³).

In some embodiments, X and X′ are each O, G¹ is a bond connecting (i)the carbon directly attached to X² and (ii) the carbon directly attachedto C(R^(2A))(R^(2B))(X⁶), G² is a bond connecting (i) the carbondirectly attached to X⁴ and (ii) the carbon directly attached toC(R^(1A))(R^(1B))(X³), and the compound has formula (A′), (B′), or (I-A)described previously.

Variables A and B

In some embodiments, A and B are each independently selected from thegroup consisting of formula (i) and formula (ii). In certainembodiments, A has formula (i), and B has formula (ii); or A has formula(ii), and B has formula (i). In other embodiments, A has formula (ii),and B has formula (ii). In still other embodiments, A has formula (i),and B has formula (i).

In some embodiments, each occurrence of Z¹ is N, and Z^(1′) is N. Insome embodiments, R⁵ is —NR^(b1)R^(c1) (e.g., —NH₂ or —NHR^(c1)). Insome embodiments, each occurrence of Z¹ is N, Z^(1′) is N, and R⁵ is—NR^(b1)R^(c1) (e.g., —NH₂ or —NHR^(c1)). In certain of theseembodiments, R⁴ and/or R⁶ is H; or R⁴ is other than H, and R⁶ is H.

In some embodiments, each occurrence of Z¹ is N, and Z^(1′) is N. Insome embodiments, R⁵ is —OH. In some embodiments, each occurrence of Z¹is N, Z^(1′) is N, and R⁵ is —OH. In certain of these embodiments, R⁶ isH. In certain of these embodiments, R⁴ is H; in other embodiments, R⁴ isother than H. For example, each occurrence of Z¹ is N; Z^(1′) is N; R⁵is —OH; R⁶ is H; and R⁴ is H.

In some embodiments, each occurrence of Z² is N, Z^(2′) is. N, and Z³ isN—R³ (e.g., N—H). In some embodiments, R^(6′) is —NR^(b1)R^(c1) (e.g.,—NH₂ or —NHR^(c1)). In some embodiments, each occurrence of Z² is N,Z^(2′) is. N, Z³ is N—R³ (e.g., N—H), and R^(6′) is —NR^(b1)R^(c1)(e.g., —NH₂ or —NHR^(c1)). In certain of these embodiments, R^(4′) is H;in other embodiments, R^(4′) is other than H.

Variables X², X³, X⁴ and X⁶

In some embodiments, each of X², X³, X⁴ and X⁶ is O.

Variables X¹ and X⁵

In some embodiments, X¹ is —OH, —OR^(a1), —F, —SH, —SR^(a1), —OC(O)H,—OC(O)R^(a1), —OC(O)NR^(b1)R^(c1); —NO₂, —N₃,—NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1), —⁺NR^(b1)R^(c1)R^(d1),—NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1),—NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1) or—NR^(d1)S(O)₂NR^(b1)R^(c1) (in certain embodiment, X¹ is other than —F).

In certain embodiments, X¹ is —OH, —OR^(a1), —OC(O)H, —OC(O)R^(a1),—OC(O)NR^(b1)R^(c1), —F, —NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), or —NR^(d1)S(O)₂NR^(b1)R^(c1)(in certain embodiment, X¹ is other than —F).

In certain embodiments, X¹ is —F, —OH, —OR^(a1), —OC(O)H, —OC(O)R^(a1),or —OC(O)NR^(b1)R^(c1) (in certain embodiment, X¹ is other than —F).

In certain embodiments, X¹ is —F, —OH or —OR^(a1) (in certainembodiment, X¹ is other than —F).

In certain embodiments, X¹ is —OH.

In other embodiments, X¹ is —NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), or —NR^(d1)S(O)₂NR^(b1)R^(c1);e.g., —NR^(b1)R^(c1) or —⁺NR^(b1)R^(c1)R^(d1); e.g., —NH₂, —⁻NH₃, orNHR^(c1).

In other embodiments, X¹ is —NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b1)R^(c1)R^(d1); —NR^(d1)C(O)H;—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), or —NR^(d1)S(O)₂NR^(b1)R^(c1);e.g., —NR^(b1)R^(c1) or —⁺NR^(b1)R^(c1)R^(d1); e.g., —NH₂, —⁻NH₃, orNHR^(c1), each of X², X³, X⁴ and X⁶ is O.

In some embodiments, the carbon directly attached to X¹ has the(R)-configuration.

In some embodiments, the carbon directly attached to X¹ has the(S)-configuration.

In some embodiments, X⁵ is —OH, —OR^(a1), —F, —SH, —SR^(a1), —OC(O)H,—OC(O)R^(a1), —OC(O)NR^(b1)R^(c1), —NO₂, —N₃,—NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1), —⁺NR^(b1)R^(c1)R^(d1),—NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1),—NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), or—NR^(d1)S(O)₂NR^(b1)R^(c1) (in certain embodiment, X⁵ is other than —F).

In certain embodiments, X⁵ is —OH, —OR^(a1), —OC(O)H, —OC(O)R^(a1),—OC(O)NR^(b1)R^(c1), —F, —NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), or —NR^(d1)S(O)₂NR^(b1)R^(c1)(in certain embodiment, X⁵ is other than —F).

In certain embodiments, X⁵ is —F, —OH, —OR^(a1), —OC(O)H, —OC(O)R^(a1),or —OC(O)NR^(b1)R^(c1) (in certain embodiment, X⁵ is other than —F).

In certain embodiments, X⁵ is —F, —OH or —OR^(a1) (in certainembodiment, X⁵ is other than —F).

In certain embodiments, X⁵ is —OH.

In other embodiments, X⁵ is —NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H, —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1),—NR^(d1)S(O)₂R^(a1), or —NR^(d1)S(O)₂NR^(b1)R^(c1); e.g., —NR^(b1)R^(c1)or —⁺NR^(b1)R^(c1)R^(d1); e.g., —NH₂, —⁻NH₃, or NHR^(c1).

In other embodiments, X⁵ is —NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R_(c1), —⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), or —NR^(d1)S(O)₂NR^(b1)R^(c1);e.g., —NR^(b1)R^(c1) or —⁺NR^(b1)R^(c1)R^(d1); e.g., —NH₂, —⁻NH₃,NHR^(c1), and each of X², X³, X⁴ and X⁶ is O.

In some embodiments, the carbon directly attached to X⁵ has the(R)-configuration.

In some embodiments, the carbon directly attached to X⁵ has the(S)-configuration.

In some embodiments, X¹ and X⁵ are each independently selected from —OH,—OR^(a1), —F, —SH, —SR^(a1), —OC(O)H, —OC(O)R^(a1), —OC(O)NR^(b1)R^(c1),—NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1),—⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1),—NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1),—NR^(d1)S(O)₂R^(a1), or —NR^(d1)S(O)₂NR^(b1)R^(c1) (in certainembodiment, X¹ and/or X⁵ is other than —F). X¹ and X⁵ can be the same ordifferent.

In certain embodiments, X¹ and X⁵ are each independently selected from—OH, —OR^(a1), —OC(O)H, —OC(O)R^(a1), —OC(O)NR^(b1)R^(c1), —F, —NO₂,—N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1),—⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1),—NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1),—NR^(d1)S(O)₂R^(a1), or —NR^(d1)S(O)₂NR^(b1)R^(c1) (in certainembodiment, X⁵ is other than —F).

In certain embodiments, X¹ and X⁵ are each independently selected from—F, —OH, —OR^(a1), —OC(O)H, —OC(O)R^(a1), or —OC(O)NR^(b1)R^(c1) (incertain embodiment, X⁵ is other than —F).

In certain embodiments, X¹ and X⁵ are each independently selected from—F, —OH or —OR^(a1) (in certain embodiment, X⁵ is other than —F).

In certain embodiments, X¹ and X⁵ are each —OH.

In other embodiments, X¹ and X⁵ are each independently selected from—NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1),—⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1),—NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1),—NR^(d1)S(O)₂R^(a1), or —NR^(d1)S(O)₂NR^(b1)R^(c1); e.g., —NR^(b1)R^(c1)or —⁺NR^(b1)R^(c1)R^(d1); e.g., —NH₂, —⁺NH₃, or NHR^(c1).

In other embodiments, X¹ and X⁵ are each independently selected from—NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1),—⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1),—NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1),—NR^(d1)S(O)₂R^(a1), or —NR^(d1)S(O)₂NR^(b1)R^(c1); e.g., —NR^(b1)R^(c1)or —⁺NR^(b1)R^(c1)R^(d1); e.g., —NH₂, —⁻NH₃, or NHR^(c1), and each ofX², X³, X⁴ and X⁶ is O.

In some embodiments, one of X¹ and X⁵ is other than —OH.

In some embodiments, one of X¹ and X⁵ is other than halo.

In some embodiments, one of X¹ and X⁵ is other than —F.

In some embodiments, one of X¹ and X⁵ is other than —OR^(a1). In certainof these embodiments, R^(a1) is:

-   -   C₁₋₁₀ alkyl optionally substituted with from 1-3 R^(A) (e.g.,        when each occurrence of R^(a1) is C₁₋₄ alkyl optionally        substituted with from 1-2 R^(A); when each occurrence of R^(a1)        is C₁₋₄ alkyl; e.g., when each occurrence of R^(a1) is methyl or        ethyl); and/or    -   heterocyclyl, including from 3-10 ring atoms, wherein from 1-3        ring atoms are independently selected from the group consisting        of nitrogen, oxygen and sulfur, and which is optionally        substituted with from 1-5 R^(C); (in certain of these        embodiments, the heterocyclyl, includes from 5-7 ring atoms;        e.g., 6 ring atoms, e.g., R^(a1) is optionally substituted        pyranyl or piperidinyl); and/or    -   (heterocyclyl as defined above)-C₁₋₆ alkylene; in certain of        these embodiments, the heterocyclyl portion includes from 5-7        ring atoms; e.g., 6 ring atoms, e.g., optionally substituted        pyranyl or piperidinyl).

In some embodiments, one of X¹ and X⁵ is other than —OC(O)R^(a1). Incertain of these embodiments, R^(a1) is:

-   -   C₁₋₁₀ alkyl optionally substituted with from 1-3 R^(A) (e.g.,        when each occurrence of R^(a1) is C₁₋₄ alkyl optionally        substituted with from 1-2 R^(A); when each occurrence of R^(a1)        is C₁₋₄ alkyl; e.g., when each occurrence of R^(a1) is methyl;        and/or    -   C₆₋₁₀ aryl (e.g., phenyl) optionally substituted with from 1-5        R^(D).

In some embodiments, one of X¹ and X⁵ is other than —OC(O)NR^(b1)R^(c1).

In some embodiments, one of X¹ and X⁵ is other than —OH and halo. Incertain embodiments, one of X¹ and X⁵ is other than —OH and —F.

In some embodiments, one of X¹ and X⁵ is other than —OH, halo (e.g.,—F), —OR^(a1), and —OC(O)R^(a1).

In some embodiments, one of X¹ and X⁵ is other than —OH, halo (e.g.,—F), —OR^(a1), —OC(O)R^(a1), and —OC(O)NR^(b1)R^(c1).

In some embodiments, one of X¹ and X⁵ is selected from the groupconsisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —NO₂, —N₃, —SH,—SR^(a1), —C(O)H, —C(O)R^(a1), —C(O)NR^(b1)R^(c1), —C(O)OH,—C(O)OR^(a1), —C(═NR^(c1)NR^(b1)R^(c1),—NR^(d1)C(═NR^(c1))NR^(b1)R^(c1), —NR^(b1)C^(c1), —⁺NR^(b2)R^(c2)R^(d2),—NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1),—NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1),—NR^(d1)S(O)₂NR^(b1)R^(c1), —S(O)R^(a1), —S(O)NR^(b1)R^(c1),—S(O)₂R^(a1), and —S(O)₂NR^(b1)R^(c1); and the other is as definedanywhere herein.

In certain embodiments, one of X¹ and X⁵ is selected from the groupconsisting of H, C₁₋₄ alkyl, C₁₋₁₄ haloalkyl, —CN, —NO₂, —N₃, —C(O)H,—C(O)R^(a1), —C(O)NR^(b1)R^(c1), —C(O)OH, —C(O)OR^(a1),—C(═NR^(e1))NR^(b1)R^(c1), —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), —NR^(d1)S(O)₂NR^(b1)R^(c1),—S(O)R^(a1), —S(O)NR^(b1)R^(c1), —S(O)₂R^(a1), and —S(O)₂NR^(b1)R^(c1);and the other is as defined anywhere herein.

In certain embodiments, one of X¹ and X⁵ is selected from the groupconsisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —NO₂, —N₃,—C(O)R^(a1), —C(O)NR^(b1)R^(c1), —C(O)OH, —C(O)OR^(a1),—C(═NR^(c1))NR^(b1)R^(c1), —NR^(d1)C(═NR^(c1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), and —NR^(d1)S(O)₂NR^(b1)R^(c1);and the other is as defined anywhere herein.

In certain embodiments, one of X¹ and X⁵ is selected from the groupconsisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —NO₂, —N₃,—NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2),—NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1),—NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), and—NR^(d1)S(O)₂NR^(b1)R^(c1); and the other is as defined anywhere herein.

In certain embodiments, one of X¹ and X⁵ is selected from the groupconsisting of —NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(a1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), and —NR^(d1)S(O)₂NR^(b1)R^(c1);and the other is as defined anywhere herein.

In certain embodiments, one of X¹ and X⁵ is selected from the groupconsisting of —NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), and —NR^(d1)S(O)₂NR^(b1)R^(c1);and the other is as defined anywhere herein.

In certain embodiments, one of X¹ and X⁵ is selected from the groupconsisting of —NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), and —NR^(d1)C(O)NR^(b1)R^(c1);and the other is as defined anywhere herein.

In certain embodiments, one of X¹ and X⁵ is selected from the groupconsisting of —NR^(b1)R^(c1) and —⁻NR^(b2)R^(c2)R^(d2); and the other isas defined anywhere herein.

In certain embodiments, one of X¹ and X⁵ is selected from the groupconsisting —NH₂, —⁺NH₃, and NHR^(c1); and the other is as definedanywhere herein.

In some embodiments, each of X¹ and X⁵ is independently selected fromthe group consisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —NO₂, —N₃,—SH, —SR^(a1), —C(O)H, —C(O)R^(a1), —C(O)NR^(b1)R^(c1), —C(O)OH,—C(O)OR^(a1), —C(═NR^(e1))NR^(b1)R^(c1),—NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2),—NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1),—NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1),—NR^(d1)S(O)₂NR^(b1)R^(c1), —S(O)R^(a1), —S(O)NR^(b1)R^(c1),—S(O)₂R^(a1), and —S(O)₂NR^(b1)R^(c1).

In certain embodiments, each of X¹ and X⁵ is independently selected fromthe group consisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —NO₂, —N₃,—C(O)H, —C(O)R^(a1), —C(O)NR^(b1)R^(c1), —C(O)OH, —C(O)OR^(a1),—C(═NR^(e1))NR^(b1)R^(c1), —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), —NR^(d1)S(O)₂NR^(b1)R^(c1),—S(O)R^(a1), —S(O)NR^(b1)R^(c1), —S(O)₂R^(a1), and —S(O)₂NR^(b1)R^(c1).

In certain embodiments, each of X¹ and X⁵ is independently selected fromthe group consisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —NO₂,N^(d3), —C(O)H, —C(O)R^(a1), —C(O)NR^(b1)R^(c1), —C(O)OH, —C(O)OR^(a1),—C(═NR^(e1))NR^(b1)R^(c1), —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), and —NR^(d1)S(O)₂NR^(b1)R^(c1).

In certain embodiments, each of X¹ and X⁵ is independently selected fromthe group consisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —CN, —NO₂, —N₃,—NR^(d1)C(═NR^(e1))NR^(b1)R^(a1), —NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2),—NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1),—NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), and—NR^(d1)S(O)₂NR^(b1)R^(c1).

In certain embodiments, each of X¹ and X⁵ is independently selected fromthe group consisting of —NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1),—NR^(b1)R^(c1), —NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2), —NR^(d1)C(O)H,—NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), and —NR^(d1)S(O)₂NR^(b1)R^(c1).

In certain embodiments, each of X¹ and X⁵ is independently selected fromthe group consisting of —NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2),—NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1),—NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), and—NR^(d1)S(O)₂NR^(b1)R^(c1).

In certain embodiments, each of X¹ and X⁵ is independently selected fromthe group consisting of —NR^(b1)R^(c1), —⁺NR^(b2)R^(c2)R^(d2),—NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1), —NR^(d1)C(O)OR^(a1), and—NR^(d1)C(O)NR^(b1)R^(c1).

In certain embodiments, each of X¹ and X⁵ is independently selected fromthe group consisting of —NR^(b1)R^(c1) and —⁺NR^(b2)R^(c2)R^(d2).

In certain embodiments, each of X¹ and X⁵ is independently selected fromthe group consisting —NH₂, —⁺NH₃, and NHR^(c1).

In some embodiments, the carbon directly attached to X¹ and the carbondirectly attached to X⁵ both have the (R)-configuration.

In some embodiments, the carbon directly attached to X¹ and the carbondirectly attached to X⁵ both have the (S)-configuration.

In some embodiments, the carbon directly attached to X¹ and the carbondirectly attached to X⁵ have opposite configurations (i.e., one has the(R)-configuration, and the other has the (S-configuration).

Variables L¹ and L²

In some embodiments, L¹ is

In some embodiments, Y¹ is —OH, —OR^(a1), O⁻, —SH, —SR^(a1), or S. Incertain embodiments, Y¹ is —OH, —OR^(a1), or O⁻ (e.g., —OR^(a1) or O⁻).In other embodiments, Y¹ is —SH or S⁻. In certain of these embodiments,L¹ has the R_(P) configuration, or L¹ has the S_(P) configuration.

In some embodiments, L² is

In some embodiments, Y² is —OH, —OR^(a1), O⁻, —SH, —SR^(a1), or S. Incertain embodiments, Y² is —OH, —OR^(a1), or O⁻ (e.g., —OR^(a1) or O⁻).In other embodiments, Y² is —SH or S⁻. In certain of these embodiments,L² has the R_(P) configuration, or L² has the S_(P) configuration.

In some embodiments, L¹ is

and L² is

Y¹ and Y² can be the same or different. In some embodiments, Y¹ and Y²are each independently selected from is —OH, —OR^(a1), O⁻, —SH,—SR^(a1), or S; e.g., —OR^(a1) or O⁻; e.g., —SH or S⁻; e.g., S⁻.

In certain embodiments, Y¹ and Y² are each O⁻.

In certain embodiments, Y¹ and Y² are each —SH or S⁻. In certain ofthese embodiments, L¹ and L² both have the R_(P) configuration or bothhave the S_(P) configuration. In other of these embodiments, one of L¹and L² has the R_(P) configuration, and the other has the S_(P)configuration.

Variables R^(1A) and R^(1B) and R^(2A) and R^(2B)

In some embodiments, R^(1A) and R^(1B) are each H. In some embodiments,R^(2A) and R^(2B) are each H. In some embodiments, R^(1A) and R^(1B) areeach H, and R^(2A) and R^(2B) are each H.

Non-Limiting Combinations

In some embodiments of formula (A), (B), (I), (A′), (B′), or (I-A):

X¹ and X⁵ are each independently selected from the group consisting of—NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1),—⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1),—NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1),—NR^(d1)S(O)R^(a1), —NR^(d1)S(O)₂R^(a1), and —NR^(d1)S(O)₂NR^(b1)R^(c1);

each of X², X³, X¹ and X⁶ is O;

L¹ is

L² is

Y¹ and Y² are each independently selected from —OH, —OR^(a1), O⁻, —SH,—SR^(a1), or S; and

A and B are each independently selected from the group consisting of:formula (i) and formula (ii).

In some embodiments of formula (A), (B), (I), (A′), (B′), or (I-A):

X¹ and X⁵ are each independently selected from the group consisting of—NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1),—⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1),—NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1),—NR^(d1)S(O)₂R^(a1), and —NR^(d1)S(O)₂NR^(b1)R^(c1);

-   -   each of X², X³, X⁴ and X⁶ is O;

L¹ is

L² is

Y¹ and Y² are each independently selected from —OH, —OR^(a1), O⁻, —SH,—SR^(a1), or S; and

A and B are each independently selected from the group consisting of:formula (i) and formula (ii);

and optionally:

each occurrence of V is N, Z^(1′) is N, and R⁵ is —NR^(b1)R^(c1) (e.g.,—NH₂ or —NHR^(c1)); and in certain of these embodiments, R⁴ and/or R⁶ isH; or R⁴ is other than H, and R⁶ is H; and/or

each occurrence of Z¹ is N, Z^(1′) is N, and R⁵ is —OH; in certain ofthese embodiments, R⁶ is H; in certain of these embodiments, R⁴ is H; inother embodiments, R⁴ is other than H; and/or

each occurrence of Z² is N, Z^(2′) is. N, Z³ is N—R³ (e.g., N—H), andR^(6′) is —NR^(b1)R^(c1) (e.g., —NH₂ or —NHR^(c1)); and in certain ofthese embodiments, R^(4′) is H; in other embodiments, R^(4′) is otherthan H.

In some embodiments, the compound has

In some embodiments, the compound has formula (V):

in which,

X¹¹ and X⁵¹ are each independently selected from the group consisting of—NO₂, —N₃, —NR^(d1)C(═NR^(e1))NR^(b1)R^(c1), —NR^(b1)R^(c1),—⁺NR^(b1)R^(c1)R^(d1), —NR^(d1)C(O)H, —NR^(d1)C(O)R^(a1),—NR^(d1)C(O)OR^(a1), —NR^(d1)C(O)NR^(b1)R^(c1), —NR^(d1)S(O)R^(a1),—NR^(d1)S(O)₂R^(a1), and —NR^(d1)S(O)₂NR^(b1)R^(c1);

each of X², X³, X¹ and X⁶ is O;

L¹ is

L² is

Y¹ and Y² are each independently selected from —OH, —OR^(a1), O⁻, —SH,—SR^(a1), or S; and

A and B are each independently selected from the group consisting of:formula (i) and formula (ii).

Representative and non-limiting examples of formula I compounds areprovided in Table 1.

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

Pharmaceutical Compositions and Administration

General

In some embodiments, a chemical entity (e.g., a compound that modulates(e.g., agonizes or partially agonizes) STING, or a pharmaceuticallyacceptable salt, and/or hydrate, and/or cocrystal, and/or drugcombination thereof) is administered as a pharmaceutical compositionthat includes the chemical entity and one or more pharmaceuticallyacceptable excipients, and optionally one or more additional therapeuticagents as described herein.

In some embodiments, the chemical entities can be administered incombination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-γ-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a chemical entity as described hereinin the range of 0.005% to 100% with the balance made up from non-toxicexcipient may be prepared. The contemplated compositions may contain0.001%-100% of a chemical entity provided herein, in one embodiment0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington: TheScience and Practice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press,London, UK. 2012).

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or apharmaceutical composition thereof can be administered to subject inneed thereof by any accepted route of administration. Acceptable routesof administration include, but are not limited to, buccal, cutaneous,endocervical, endosinusial, endotracheal, enteral, epidural,interstitial, intra-abdominal, intra-arterial, intrabronchial,intrabursal, intracerebral, intracisternal, intracoronary, intradermal,intraductal, intraduodenal, intradural, intraepidermal, intraesophageal,intragastric, intragingival, intraileal, intralymphatic, intramedullary,intrameningeal, intramuscular, intraovarian, intraperitoneal,intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial,intratesticular, intrathecal, intratubular, intratumoral, intrauterine,intravascular, intravenous, nasal, nasogastric, oral, parenteral,percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous,sublingual, submucosal, topical, transdermal, transmucosal,transtracheal, ureteral, urethral and vaginal. In certain embodiments, apreferred route of administration is parenteral (e.g., intratumoral).

Compositions can be formulated for parenteral administration, e.g.,formulated for injection via the intravenous, intramuscular,sub-cutaneous, or even intraperitoneal routes. Typically, suchcompositions can be prepared as injectables, either as liquid solutionsor suspensions; solid forms suitable for use to prepare solutions orsuspensions upon the addition of a liquid prior to injection can also beprepared; and the preparations can also be emulsified. The preparationof such formulations will be known to those of skill in the art in lightof the present disclosure.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions; formulations including sesame oil,peanut oil, or aqueous propylene glycol; and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that it may be easily injected. It also should be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms, such as bacteria andfungi.

The carrier also can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion, and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques, which yield a powder of the active ingredient, plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Intratumoral injections are discussed, e.g., in Lammers, et al., “Effectof Intratumoral Injection on the Biodistribution and the TherapeuticPotential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.2006, 10, 788-795.

Pharmacologically acceptable excipients usable in the rectal compositionas a gel, cream, enema, or rectal suppository, include, withoutlimitation, any one or more of cocoa butter glycerides, syntheticpolymers such as polyvinylpyrrolidone, PEG (like PEG ointments),glycerine, glycerinated gelatin, hydrogenated vegetable oils,poloxamers, mixtures of polyethylene glycols of various molecularweights and fatty acid esters of polyethylene glycol Vaseline, anhydrouslanolin, shark liver oil, sodium saccharinate, menthol, sweet almondoil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil,aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodiumpropyl p-oxybenzoate, diethylamine, carbomers, carb op ol, m ethyl oxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropylalcohol, propylene glycol, liquid paraffin, xanthan gum,carboxy-metabisulfite, sodium edetate, sodium benzoate, potassiummetabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM),lactic acid, glycine, vitamins, such as vitamin A and E and potassiumacetate.

In certain embodiments, suppositories can be prepared by mixing thechemical entities described herein with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid atbody temperature and therefore melt in the rectum and release the activecompound. In other embodiments, compositions for rectal administrationare in the form of an enema.

In other embodiments, the compounds described herein or a pharmaceuticalcomposition thereof are suitable for local delivery to the digestive orGI tract by way of oral administration (e.g., solid or liquid dosageforms.).

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the chemicalentity is mixed with one or more pharmaceutically acceptable excipients,such as sodium citrate or dicalcium phosphate and/or: a) fillers orextenders such as starches, lactose, sucrose, glucose, mannitol, andsilicic acid, b) binders such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c)humectants such as glycerol, d) disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, and sodium carbonate, e) solution retarding agents such asparaffin, f) absorption accelerators such as quaternary ammoniumcompounds, g) wetting agents such as, for example, cetyl alcohol andglycerol monostearate, h) absorbents such as kaolin and bentonite clay,and i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a chemical entity provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or more chemicalentities provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Other physiologically acceptable compounds include wetting agents,emulsifying agents, dispersing agents or preservatives that areparticularly useful for preventing the growth or action ofmicroorganisms. Various preservatives are well known and include, forexample, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free ofundesirable matter. These compositions can be sterilized byconventional, well-known sterilization techniques. For various oraldosage form excipients such as tablets and capsules sterility is notrequired. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include oneor more components that chemically and/or structurally predispose thecomposition for delivery of the chemical entity to the stomach or thelower GI; e.g., the ascending colon and/or transverse colon and/ordistal colon and/or small bowel. Exemplary formulation techniques aredescribed in, e.g., Filipski, K. J., et al., Current Topics in MedicinalChemistry, 2013, 13, 776-802, which is incorporated herein by referencein its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill(Intec Pharma), floating capsules, and materials capable of adhering tomucosal walls.

Other examples include lower-GI targeting techniques. For targetingvarious regions in the intestinal tract, several enteric/pH-responsivecoatings and excipients are available. These materials are typicallypolymers that are designed to dissolve or erode at specific pH ranges,selected based upon the GI region of desired drug release. Thesematerials also function to protect acid labile drugs from gastric fluidor limit exposure in cases where the active ingredient may be irritatingto the upper GI (e.g., hydroxypropyl methylcellulose phthalate series,Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate,hydroxypropyl methylcellulose acetate succinate, Eudragit series(methacrylic acidmethyl methacrylate copolymers), and Marcoat). Othertechniques include dosage forms that respond to local flora in the GItract, Pressure-controlled colon delivery capsule, and Pulsincap.

Ocular compositions can include, without limitation, one or more of anyof the following: viscogens (e.g., Carboxymethylcellulose, Glycerin,Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic(triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkoniumchloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zincchloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorocomplex; Allergan, Inc.)).

Topical compositions can include ointments and creams. Ointments aresemisolid preparations that are typically based on petrolatum or otherpetroleum derivatives. Creams containing the selected active agent aretypically viscous liquid or semisolid emulsions, often eitheroil-in-water or water-in-oil. Cream bases are typically water-washable,and contain an oil phase, an emulsifier and an aqueous phase. The oilphase, also sometimes called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol; the aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant. As with other carriers or vehicles,an ointment base should be inert, stable, nonirritating andnon-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositionsdescribed herein can include one or more one or more of the following:lipids, interbilayer crosslinked multilamellar vesicles, biodegradeablepoly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-basednanoparticles or microparticles, and nanoporous particle-supported lipidbilayers.

Dosages

The dosages may be varied depending on the requirement of the patient,the severity of the condition being treating and the particular compoundbeing employed. Determination of the proper dosage for a particularsituation can be determined by one skilled in the medical arts. Thetotal daily dosage may be divided and administered in portionsthroughout the day or by means providing continuous delivery.

In some embodiments, the compounds described herein are administered ata dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kgto about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg;from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about 150 mg/Kg; fromabout 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg toabout 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1mg/Kg to about 0.5 mg/Kg).

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as asingle dose or as two or more divided doses) or non-daily basis (e.g.,every other day, every two days, every three days, once weekly, twiceweeks, once every two weeks, once a month).

In some embodiments, the period of administration of a compounddescribed herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more. In an embodiment, a therapeutic compound isadministered to an individual for a period of time followed by aseparate period of time. In another embodiment, a therapeutic compoundis administered for a first period and a second period following thefirst period, with administration stopped during the second period,followed by a third period where administration of the therapeuticcompound is started and then a fourth period following the third periodwhere administration is stopped. In an aspect of this embodiment, theperiod of administration of a therapeutic compound followed by a periodwhere administration is stopped is repeated for a determined orundetermined period of time. In a further embodiment, a period ofadministration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more.

Methods of Treatment

In some embodiments, methods for treating a subject having condition,disease or disorder in which a decrease or increase in STING activity(e.g., a decrease, e.g., repressed or impaired STING signaling)contributes to the pathology and/or symptoms and/or progression of thecondition, disease or disorder (e.g., immune disorders, cancer) areprovided. In certain embodiments, the chemical entities described hereininduce an immune response in a subject (e.g., a human). In certainembodiments, the chemical entities described herein induceSTING-dependent type I interferon production in a subject (e.g., ahuman).

Indications

In some embodiments, the condition, disease or disorder is cancer.Non-limiting examples of cancer include melanoma, carcinoma, lymphoma,blastoma, sarcoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include breast cancer, colon cancer,rectal cancer, colorectal cancer, kidney or renal cancer, clear cellcancer lung cancer including small-cell lung cancer, non-small cell lungcancer, adenocarcinoma of the lung and squamous carcinoma of the lung,squamous cell cancer (e.g. epithelial squamous cell cancer), cervicalcancer, ovarian cancer, prostate cancer, prostatic neoplasms, livercancer, bladder cancer, cancer of the peritoneum, hepatocellular cancer,gastric or stomach cancer including gastrointestinal cancer,gastrointestinal stromal tumor, pancreatic cancer, head and neck cancer,glioblastoma, retinoblastoma, astrocytoma, thecomas, arrhenoblastomas,hepatoma, hematologic malignancies including non-Hodgkins lymphoma(NHL), multiple myeloma, myelodysplasia disorders, myeloproliferativedisorders, chronic myelogenous leukemia, and acute hematologicmalignancies, endometrial or uterine carcinoma, endometriosis,endometrial stromal sarcoma, fibrosarcomas, choriocarcinoma, salivarygland carcinoma, vulval cancer, thyroid cancer, esophageal carcinomas,hepatic carcinoma, anal carcinoma, penile carcinoma, nasopharyngealcarcinoma, laryngeal carcinomas, Kaposi's sarcoma, mast cell sarcoma,ovarian sarcoma, uterine sarcoma, melanoma, malignant mesothelioma, skincarcinomas, Schwannoma, oligodendroglioma, neuroblastomas,neuroectodermal tumor, rhabdomyosarcoma, osteogenic sarcoma,leiomyosarcomas, Ewing Sarcoma, peripheral primitive neuroectodermaltumor, urinary tract carcinomas, thyroid carcinomas, Wilm's tumor, aswell as abnormal vascular proliferation associated with phakomatoses,edema (such as that associated with brain tumors), and Meigs' syndrome.In some cases, the cancer is melanoma.

In some embodiments, the condition, disease or disorder is aneurological disorder, which includes disorders that involve the centralnervous system (brain, brainstem and cerebellum), the peripheral nervoussystem (including cranial nerves), and the autonomic nervous system(parts of which are located in both central and peripheral nervoussystem). Non-limiting examples of cancer include acquired epileptiformaphasia; acute disseminated encephalomyelitis; adrenoleukodystrophy;age-related macular degeneration; agenesis of the corpus callosum;agnosia; Aicardi syndrome; Alexander disease; Alpers' disease;alternating hemiplegia; Alzheimer's disease; Vascular dementia;amyotrophic lateral sclerosis; anencephaly; Angelman syndrome;angiomatosis; anoxia; aphasia; apraxia; arachnoid cysts; arachnoiditis;Anronl-Chi ari malformation; arteriovenous malformation; Aspergersyndrome; ataxia telegiectasia; attention deficit hyperactivitydisorder; autism; autonomic dysfunction; back pain; Batten disease;Behcet's disease; Bell's palsy; benign essential blepharospasm; benignfocal; amyotrophy; benign intracranial hypertension; Binswanger'sdisease; blepharospasm; Bloch Sulzberger syndrome; brachial plexusinjury; brain abscess; brain injury; brain tumors (includingglioblastoma multiforme); spinal tumor; Brown-Sequard syndrome; Canavandisease; carpal tunnel syndrome; causalgia; central pain syndrome;central pontine myelinolysis; cephalic disorder; cerebral aneurysm;cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism;cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-inducedneuropathy and neuropathic pain; Chiari malformation; chorea; chronicinflammatory demyelinating polyneuropathy; chronic pain; chronicregional pain syndrome; Coffin Lowry syndrome; coma, includingpersistent vegetative state; congenital facial diplegia; corticobasaldegeneration; cranial arteritis; craniosynostosis; Creutzfeldt-Jakobdisease; cumulative trauma disorders; Cushing's syndrome; cytomegalicinclusion body disease; cytomegalovirus infection; dancing eyes-dancingfeet syndrome; Dandy-Walker syndrome; Dawson disease; De Morsier'ssyndrome; Dejerine-Klumke palsy; dementia; dermatomyositis; diabeticneuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia;dystonias; early infantile epileptic encephalopathy; empty sellasyndrome; encephalitis; encephaloceles; encephalotrigeminalangiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry's disease;Fahr's syndrome; fainting; familial spastic paralysis; febrile seizures;Fisher syndrome; Friedreich's ataxia; fronto-temporal dementia and other“tauopathies”; Gaucher's disease; Gerstmann's syndrome; giant cellarteritis; giant cell inclusion disease; globoid cell leukodystrophy;Guillain-Barre syndrome; HTLV-1-associated myelopathy;Hallervorden-Spatz disease; head injury; headache; hemifacial spasm;hereditary spastic paraplegia; heredopathia atactica polyneuritiformis;herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associateddementia and neuropathy (also neurological manifestations of AIDS);holoprosencephaly; Huntington's disease and other polyglutamine repeatdiseases; hydranencephaly; hydrocephalus; hypercortisolism; hypoxia;immune-mediated encephalomyelitis; inclusion body myositis;incontinentia pigmenti; infantile phytanic acid storage disease;infantile refsum disease; infantile spasms; inflammatory myopathy;intracranial cyst; intracranial hypertension; Joubert syndrome;Kearns-Sayre syndrome; Kennedy disease Kinsbourne syndrome; Klippel Feilsyndrome; Krabbe disease; Kugelberg-Welander disease; kuru; Laforadisease; Lambert-Eaton myasthenic syndrome; Landau-Kleffner syndrome;lateral medullary (Wallenberg) syndrome; learning disabilities; Leigh'sdisease; Lennox-Gustaut syndrome; Lesch-Nyhan syndrome; leukodystrophy;Lewy body dementia; Lissencephaly; locked-in syndrome; Lou Gehrig'sdisease (i.e., motor neuron disease or amyotrophic lateral sclerosis);lumbar disc disease; Lyme diseaseneurological sequelae; Machado-Josephdisease; macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome;Menieres disease; meningitis; Menkes disease; metachromaticleukodystrophy; microcephaly; migraine; Miller Fisher syndrome;mini-strokes; mitochondrial myopathies; Mobius syndrome; monomelicamyotrophy; motor neuron disease; Moyamoya disease;mucopolysaccharidoses; milti-infarct dementia; multifocal motorneuropathy; multiple sclerosis and other demyelinating disorders;multiple system atrophy with postural hypotension; p muscular dystrophy;myasthenia gravis; myelinoclastic diffuse sclerosis; myoclonicencephalopathy of infants; myoclonus; myopathy; myotonia congenital;narcolepsy; neurofibromatosis; neuroleptic malignant syndrome;neurological manifestations of AIDS; neurological sequelae of lupus;neuromyotonia; neuronal ceroid lipofuscinosis; neuronal migrationdisorders; Niemann-Pick disease; O'Sullivan-McLeod syndrome; occipitalneuralgia; occult spinal dysraphism sequence; Ohtahara syndrome;olivopontocerebellar atrophy; opsoclonus myoclonus; optic neuritis;orthostatic hypotension; overuse syndrome; paresthesia; Parkinson'sdisease; paramyotonia congenital; paraneoplastic diseases; paroxysmalattacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease; periodicparalyses; peripheral neuropathy; painful neuropathy and neuropathicpain; persistent vegetative state; pervasive developmental disorders;photic sneeze reflex; phytanic acid storage disease; Pick's disease;pinched nerve; pituitary tumors; polymyositis; porencephaly; post-poliosyndrome; postherpetic neuralgia; postinfectious encephalomyelitis;postural hypotension; Prader-Willi syndrome; primary lateral sclerosis;prion diseases; progressive hemifacial atrophy; progressive multifocalleukoencephalopathy; progressive sclerosing poliodystrophy; progressivesupranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (types Iand II); Rasmussen's encephalitis; reflex sympathetic dystrophysyndrome; Refsum disease; repetitive motion disorders; repetitive stressinjuries; restless legs syndrome; retrovirus-associated myelopathy; Rettsyndrome; Reye's syndrome; Saint Vitus dance; Sandhoff disease;Schilder's disease; schizencephaly; septo-optic dysplasia; shaken babysyndrome; shingles; Shy-Drager syndrome; Sjögren's syndrome; sleepapnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury;spinal cord tumors; spinal muscular atrophy; Stiff-Person syndrome;stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis;subcortical arteriosclerotic encephalopathy; Sydenham chorea; syncope;syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporalarteritis; tethered spinal cord syndrome; Thomsen disease; thoracicoutlet syndrome; Tic Douloureux; Todd's paralysis; Tourette syndrome;transient ischemic attack; transmissible spongiform encephalopathies;transverse myelitis; traumatic brain injury; tremor; trigeminalneuralgia; tropical spastic paraparesis; tuberous sclerosis; vasculardementia (multi-infarct dementia); vasculitis including temporalarteritis; Von Hippel-Lindau disease; Wallenberg's syndrome;Werdnig-Hoffman disease; West syndrome; whiplash; Williams syndrome;Wildon's disease; and Zellweger syndrome.

In some embodiments, the condition, disease or disorder is an autoimmunediseases. Non-limiting examples include rheumatoid arthritis, systemiclupus erythematosus, multiple sclerosis, inflammatory bowel diseases(IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), whichare chronic inflammatory conditions with polygenic susceptibility. Incertain embodiments, the condition is an inflammatory bowel disease. Incertain embodiments, the condition is Crohn's disease, autoimmunecolitis, iatrogenic autoimmune colitis, ulcerative colitis, colitisinduced by one or more chemotherapeutic agents, colitis induced bytreatment with adoptive cell therapy, colitis associated by one or morealloimmune diseases (such as graft-vs-host disease, e.g., acute graftvs. host disease and chronic graft vs. host disease), radiationenteritis, collagenous colitis, lymphocytic colitis, microscopiccolitis, and radiation enteritis. In certain of these embodiments, thecondition is alloimmune disease (such as graft-vs-host disease, e.g.,acute graft vs. host disease and chronic graft vs. host disease), celiacdisease, irritable bowel syndrome, rheumatoid arthritis, lupus,scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, andmucositis (e.g., oral mucositis, esophageal mucositis or intestinalmucositis).

In some embodiments, modulation of the immune system by STING providesfor the treatment of diseases, including diseases caused by foreignagents. Exemplary infections by foreign agents which may be treatedand/or prevented by the method of the present invention include aninfection by a bacterium (e.g., a Gram-positive or Gram-negativebacterium), an infection by a fungus, an infection by a parasite, and aninfection by a virus. In one embodiment of the present invention, theinfection is a bacterial infection (e.g., infection by E. coli,Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp.,Staphylococcus aureus, Streptococcus spp., or vancomycin-resistantenterococcus). In another embodiment, the infection is a fungalinfection (e.g. infection by a mould, a yeast, or a higher fungus). Instill another embodiment, the infection is a parasitic infection (e.g.,infection by a single-celled or multicellular parasite, includingGiardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, andToxoplasma gondiz). In yet another embodiment, the infection is a viralinfection (e.g., infection by a virus associated with AIDS, avian flu,chickenpox, cold sores, common cold, gastroenteritis, glandular fever,influenza, measles, mumps, pharyngitis, pneumonia, rubella, SARS, andlower or upper respiratory tract infection (e.g., respiratory syncytialvirus)).

In some embodiments, the condition, disease or disorder is hepatits B(see, e.g., WO 2015/061294).

In some embodiments, the condition, disease or disorder is mucositis,also known as stomatitits, which can occur as a result of chemotherapyor radiation therapy, either alone or in combination as well as damagecaused by exposure to radiation outside of the context of radiationtherapy.

In some embodiments, the condition, disease or disorder is uveitis,which is inflammation of the uvea (e.g., anterior uveitis, e.g.,iridocyclitis or iritis; intermediate uveitis (also known as parsplanitis); posterior uveitis; or chorioretinitis, e.g., pan-uveitis).

Combination Therapy

This disclosure contemplates both monotherapy regimens as well ascombination therapy regimens.

In some embodiments, the methods described herein can further includeadministering one or more additional therapies (e.g., one or moreadditional therapeutic agents and/or one or more therapeutic regimens)in combination with administration of the compounds described herein.

In certain embodiments, the methods described herein can further includeadministering one or more additional cancer therapies.

The one or more additional cancer therapies can include, withoutlimitation, surgery, radiotherapy, chemotherapy, toxin therapy,immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine,hepatitis B vaccine, Oncophage, Provenge) and gene therapy, as well ascombinations thereof. Immunotherapy, including, without limitation,adoptive cell therapy, the derivation of stem cells and/or dendriticcells, blood transfusions, lavages, and/or other treatments, including,without limitation, freezing a tumor.

In some embodiments, the one or more additional cancer therapies ischemotherapy, which can include administering one or more additionalchemotherapeutic agents.

In certain embodiments, the additional chemotherapeutic agent is animmunomodulatory moiety, e.g., an immune checkpoint inhibitor. Incertain of these embodiments, the immune checkpoint inhibitor targets animmune checkpoint receptor selected from the group consisting of CTLA-4,PD-1, PD-L1, PD-1 PD-L1, PD-1 PD-L2, interleukin-2 (IL-2), indoleamine2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), Tcell immunoglobulin and mucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3,Phosphatidylserine-TIM3, lymphocyte activation gene 3 protein (LAG3),MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITRligand GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT,HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244,ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2,Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR familymembers, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244,CD28, CD86-CD28, CD86-CTLA, CD80-CD28, CD39, CD73 Adenosine-CD39-CD73,CXCR4-CXCL12, Phosphatidylserine, TIM₃, Phosphatidylserine-TIM₃,SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, and CD155; e.g., CTLA-4 orPD1 or PD-L1). See, e.g., Postow, M. J. Clin. Oncol. 2015, 33, 1.

In certain of these embodiments, the immune checkpoint inhibitor isselected from the group consisting of: Urelumab, PF-05082566, MEDI6469,TRX518, Varlilumab, CP-870893, Pembrolizumab (PD1), Nivolumab (PD1),Atezolizumab (formerly MPDL3280A) (PDL1), MEDI4736 (PD-L1), Avelumab(PD-L1), PDR001 (PD1), BMS-986016, MGA271, Lirilumab, IPH2201,Emactuzumab, INCB024360, Galunisertib, Ulocuplumab, BKT140, Bavituximab,CC-90002, Bevacizumab, and 1VINRP1685A, and MGA271.

In certain embodiments, the additional chemotherapeutic agent is a STINGagonist. For example, the STING agonist can comprise a flavonoid.Suitable flavonoids include, but are not limited to,10-(carboxymethyl)-9(10H)acridone (CMA), 5,6-Dimethylxanthenone-4-aceticacid (DMXAA), methoxyvone, 6,4′-dimethoxyflavone, 4′-methoxyflavone,3′,6′-dihydroxyflavone, 7,2′-dihydroxyflavone, daidzein, formononetin,retusin 7-methyl ether, xanthone, or any combination thereof. In someaspects, the STING agonist can be 10-(carboxymethyl)-9(10H)acridone(CMA). In some aspects, the STING agonist can be5,6-Dimethylxanthenone-4-acetic acid (DMXAA). In some aspects, the STINGagonist can be methoxyvone. In some aspects, the STING agonist can be6,4′-dimethoxyflavone. In some aspects, the STING agonist can be4′-methoxyflavone. In some aspects, the STING agonist can be3′,6′-dihydroxyflavone. In some aspects, the STING agonist can be7,2′-dihydroxyflavone. In some aspects, the STING agonist can bedaidzein. In some aspects, the STING agonist can be formononetin. Insome aspects, the STING agonist can be retusin 7-methyl ether. In someaspects, the STING agonist can be xanthone. In some aspects, the STINGagonist can be any combination of the above flavonoids. Thus, forexample, in some embodiments the flavonoid comprises DMXAA.

In certain embodiments, the additional chemotherapeutic agent is analkylating agent. Alkylating agents are so named because of theirability to alkylate many nucleophilic functional groups under conditionspresent in cells, including, but not limited to cancer cells. In afurther embodiment, an alkylating agent includes, but is not limited to,Cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil,ifosfamide and/or oxaliplatin. In an embodiment, alkylating agents canfunction by impairing cell function by forming covalent bonds with theamino, carboxyl, sulfhydryl, and phosphate groups in biologicallyimportant molecules or they can work by modifying a cell's DNA. In afurther embodiment an alkylating agent is a synthetic, semisynthetic orderivative.

In certain embodiments, the additional chemotherapeutic agent is ananti-metabolite. Anti-metabolites masquerade as purines or pyrimidines,the building-blocks of DNA and in general, prevent these substances frombecoming incorporated in to DNA during the “S” phase (of the cellcycle), stopping normal development and division. Anti-metabolites canalso affect RNA synthesis. In an embodiment, an antimetabolite includes,but is not limited to azathioprine and/or mercaptopurine. In a furtherembodiment an anti-metabolite is a synthetic, semisynthetic orderivative.

In certain embodiments, the additional chemotherapeutic agent is a plantalkaloid and/or terpenoid. These alkaloids are derived from plants andblock cell division by, in general, preventing microtubule function. Inan embodiment, a plant alkaloid and/or terpenoid is a vinca alkaloid, apodophyllotoxin and/or a taxane. Vinca alkaloids, in general, bind tospecific sites on tubulin, inhibiting the assembly of tubulin intomicrotubules, generally during the M phase of the cell cycle. In anembodiment, a vinca alkaloid is derived, without limitation, from theMadagascar periwinkle, Catharanthus roseus (formerly known as Vincarosea). In an embodiment, a vinca alkaloid includes, without limitation,Vincristine, Vinblastine, Vinorelbine and/or Vindesine. In anembodiment, a taxane includes, but is not limited, to Taxol, Paclitaxeland/or Docetaxel. In a further embodiment a plant alkaloid or terpernoidis a synthetic, semisynthetic or derivative. In a further embodiment, apodophyllotoxin is, without limitation, an etoposide and/or teniposide.In an embodiment, a taxane is, without limitation, docetaxel and/orortataxel. [021] In an embodiment, a cancer therapeutic is atopoisomerase. Topoisomerases are essential enzymes that maintain thetopology of DNA. Inhibition of type I or type II topoisomerasesinterferes with both transcription and replication of DNA by upsettingproper DNA supercoiling. In a further embodiment, a topoisomerase is,without limitation, a type I topoisomerase inhibitor or a type IItopoisomerase inhibitor. In an embodiment a type I topoisomeraseinhibitor is, without limitation, a camptothecin. In another embodiment,a camptothecin is, without limitation, exatecan, irinotecan, lurtotecan,topotecan, BNP 1350, CKD 602, DB 67 (AR67) and/or ST 1481. In anembodiment, a type II topoisomerase inhibitor is, without limitation,epipodophyllotoxin. In a further embodiment an epipodophyllotoxin is,without limitation, an amsacrine, etoposid, etoposide phosphate and/orteniposide. In a further embodiment a topoisomerase is a synthetic,semisynthetic or derivative, including those found in nature such as,without limitation, epipodophyllotoxins, substances naturally occurringin the root of American Mayapple (Podophyllum peltatum).

In certain embodiments, the additional chemotherapeutic agent is astilbenoid. In a further embodiment, a stilbenoid includes, but is notlimited to, Resveratrol, Piceatannol, Pinosylvin, Pterostilbene,Alpha-Viniferin, Ampelopsin A, Ampelopsin E, Diptoindonesin C,Diptoindonesin F, Epsilon-Vinferin, Flexuosol A, Gnetin H, HemsleyanolD, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid andDiptoindonesin A. In a further embodiment a stilbenoid is a synthetic,semisynthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is acytotoxic antibiotic. In an embodiment, a cytotoxic antibiotic is,without limitation, an actinomycin, an anthracenedione, ananthracycline, thalidomide, dichloroacetic acid, nicotinic acid,2-deoxyglucose and/or chlofazimine. In an embodiment, an actinomycin is,without limitation, actinomycin D, bacitracin, colistin (polymyxin E)and/or polymyxin B. In another embodiment, an antracenedione is, withoutlimitation, mitoxantrone and/or pixantrone. In a further embodiment, ananthracycline is, without limitation, bleomycin, doxorubicin(Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin,mitomycin, plicamycin and/or valrubicin. In a further embodiment acytotoxic antibiotic is a synthetic, semisynthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent isselected from endostatin, angiogenin, angiostatin, chemokines,angioarrestin, angiostatin (plasminogen fragment), basement-membranecollagen-derived anti-angiogenic factors (tumstatin, canstatin, orarrestin), anti-angiogenic antithrombin III, signal transductioninhibitors, cartilage-derived inhibitor (CDI), CD59 complement fragment,fibronectin fragment, gro-beta, heparinases, heparin hexasaccharidefragment, human chorionic gonadotropin (hCG), interferonalpha/beta/gamma, interferon inducible protein (IP-10), interleukin-12,kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs),2-methoxyestradiol, placental ribonuclease inhibitor, plasminogenactivator inhibitor, platelet factor-4 (PF4), prolactin 16 kD fragment,proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-beta(TGF-β), vasculostatin, vasostatin (calreticulin fragment) and the like.

In certain embodiments, the additional chemotherapeutic agent isselected from abiraterone acetate, altretamine, anhydrovinblastine,auristatin, bexarotene, bicalutamide, BMS 184476,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,bleomycin,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide,cachectin, cemadotin, chlorambucil, cyclophosphamide,3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol,docetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin,cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC),dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin(adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide,hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lonidamine,lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard),melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin,mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel,prednimustine, procarbazine, RPR109881, stramustine phosphate,tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine,vindesine sulfate, and vinflunine.

In certain embodiments, the additional chemotherapeutic agent isplatinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil, azathioprine, mercaptopurine,vincristine, vinblastine, vinorelbine, vindesine, etoposide andteniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine,etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin,methotrexate, gemcitabine, taxane, leucovorin, mitomycin C,tegafur-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide anddoxorubicin. Additional agents include inhibitors of mTOR (mammaliantarget of rapamycin), including but not limited to rapamycin,everolimus, temsirolimus and deforolimus.

In still other embodiments, the additional chemotherapeutic agent can beselected from those delineated in U.S. Pat. No. 7,927,613, which isincorporated herein by reference in its entirety.

In certain embodiments, the second therapeutic agent or regimen isadministered to the subject prior to contacting with or administeringthe chemical entity (e.g., about one hour prior, or about 6 hours prior,or about 12 hours prior, or about 24 hours prior, or about 48 hoursprior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen isadministered to the subject at about the same time as contacting with oradministering the chemical entity. By way of example, the secondtherapeutic agent or regimen and the chemical entity are provided to thesubject simultaneously in the same dosage form. As another example, thesecond therapeutic agent or regimen and the chemical entity are providedto the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen isadministered to the subject after contacting with or administering thechemical entity (e.g., about one hour after, or about 6 hours after, orabout 12 hours after, or about 24 hours after, or about 48 hours after,or about 1 week after, or about 1 month after).

Patient Selection

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of suchtreatment (e.g., by way of biopsy, endoscopy, or other conventionalmethod known in the art). In certain embodiments, the STING protein canserve as a biomarker for certain types of cancer, e.g., colon cancer andprostate cancer. In other embodiments, identifying a subject can includeassaying the patient's tumor microenvironment for the absence of T-cellsand/or presence of exhausted T-cells, e.g., patients having one or morecold tumors. Such patients can include those that are resistant totreatment with checkpoint inhibitors. In certain embodiments, suchpatients can be treated with a chemical entity herein, e.g., to recruitT-cells into the tumor, and in some cases, further treated with one ormore checkpoint inhibitors, e.g., once the T-cells become exhausted.

In some embodiments, the chemical entities, methods, and compositionsdescribed herein can be administered to certain treatment-resistantpatient populations (e.g., patients resistant to checkpoint inhibitors;e.g., patients having one or more cold tumors, e.g., tumors lackingT-cells or exhausted T-cells).

Compound Preparation and Biological Assays

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. For example, the compounds described hereincan be synthesized using methods described in, e.g., US 2015/0056224,the contents of each of which are hereby incorporated by reference intheir entirety. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and R G M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof. Compounds can be assayed usingthe procedures described in, e.g., WO 2015/077354.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

What is claimed is:
 1. A compound which is


2. A pharmaceutical composition comprising a compound according to claim1 or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers, diluents or excipients.